Obesity and diabetes are enormous clinical problems with global relevance. The overall goal of this proposal is to define how adipose tissue fatty acid synthase (FAS) affects obesity and diabetes. We have generated mice with fat-specific knockout of FAS (FASKOF). These mice appear to be protected from high fat diet- induced obesity and insulin resistance, and FAS depletion results in decreased expression of adipogenic genes, increased expression of MyoD (characteristic of muscle), and increased expression of fatty acid oxidation genes in adipose tissue. We hypothesize that adipose tissue FAS regulates adiposity by modulating a switch between adipogenesis and myogenesis. We further hypothesize that the increased fatty acid oxidation in FASKOF mice requires activation of PPARalpha, an important regulator of glucose and lipid metabolism. We propose the following specific aims to test these hypotheses: Aim 1. Characterization of FASKOF mice in dietary and genetic models of obesity and diabetes. Glucose and lipid metabolism will be studied after induction of diet-induced obesity and after crossing FASKOF mice with db/db mice, a genetic model of diabetes and obesity. Aim 2. Determine if FAS modulates a switch between adipogenesis and myogenesis. We will deplete FAS in mouse primary embryonic fibroblasts and study effects on adipogenesis and myogenesis. Because the small G-protein Rho is a critical determinant of the adipogenesis-myogenesis decision, we will test the possibility that FAS regulates Rho activity by mediating its palmitoylation. Aim 3. Determine if FAS affects PPARalpha activation in adipose tissue. Recent work from our laboratory suggests that FAS in liver and brain regulates activation of PPARalpha, a nuclear receptor controlling fatty acid oxidation. To determine if FAS regulates PPARalpha in adipose tissue, we will treat FASKOF mice with PPARalpha activators. We will also cross the FASKOF mice with the PPARalpha knockout mice and assess effects on metabolism and adiposity. PUBLIC HEALTH RELEVANCE: Obesity and its associated metabolic disorders represent a major public health problem. Findings from the studies proposed in this application may lead to novel therapeutic approaches to the treatment of these morbidities.